1. Field of the Invention
The present invention relates to the method for treatment of cancer using 2-hydroxyarylamide derivative or a pharmaceutically acceptable salt thereof.
2. Description of the Related Art
In the clinical treatment of cancer patients, side effects accompanied particularly by chemo-therapy and radio-therapy are the major problem. So, it is an urgent request to develop an anticancer agent to reduce side effects accompanied by chemo-therapy. If only the gene products only expressed or specifically over-expressed in cancer cells are identified and if their expressions are inhibited without destroying cell differentiation or cell metabolism in normal cells, an anticancer agent that kills cancer cells specifically without destroying normal cells would be developed based on that. Thus, it is regarded as a promising method for the development of an anticancer agent having excellent therapeutic effect with less side effects to identify a protein expressed by an oncogene or a tumor suppressor gene inducing abnormal functioning of signal transduction pathway so as to convert the malfunctioning signal transduction pathway into normal functioning one.
In particular, the importance of a protease as a tumor and cancer related factor is increased day by day. Cell growth, angiogenesis, infiltration, migration, metastasis, survival, expansion, and progression of cancer cells are all mediated by signal transduction control system and proteolytic activities of various proteases. One of the most peculiar phenomenon is degradation and remodeling of extracellular matrix composing intercellular space matrix and basement membrane by unregulated protease. Cancer cells infiltrate into the neighboring tissues locally and far away by the said system. Infiltration and metastasis of cancer cells are clinically very important factors to determine the treatment prognosis of cancer patients.
Infiltration of cancer cells composed of three serial steps of adhesion, degradation of basement membrane, and migration is essential not only for metastasis but also for angiogenesis. For example in metastasis, cancer cell infiltration is inevitable process for cancer cells to migrate into blood stream or to other tissues through blood stream. Precisely, cancer cells are adhered on the adhesion molecule expressed on basement membrane and then induce the secretion of various proteases to decompose the basement membrane thereon, leading to the migration through the broken basement membrane. Marimastat, the inhibitor belonging to matrix metalloproteinase family, which is involved in the protein decomposition essential for cell infiltration, has been known to inhibit metastasis and angiogenesis as well by inhibiting cancer cell infiltration.
Therefore, protease can regulate cancer cell metastasis and those genes involved in the same can be used as cancer prognostic markers, suggesting that protease or those genes involved in the same are important targets of cancer treatment. The most representative metastasis related proteins are MMPs (matrix metalloproteinases), cathepsin B, cathepsin D, and serine protease including uPA (urokinase plasminogen activator) (non-patent reference 1). Among many proteases, TMPRSS4 has recently been identified in its biological functions to cancer (non-patent reference 2). According to the recent reports, TMPRSS4 is an important mediator for infiltration, metastasis, migration, and adhesion as well as EMP (epithelial mesenchymal transition) in human epithelial cancer cells. It has been pointed therefore that TMPRSS4 has a great potential as a target of cancer treatment. Nevertheless, studies on TMPRSS4 are not plenty enough. Considering the great potential of TMPRSS4 as a powerful and independent prognostic marker and as a target for the development of an inhibitor of infiltration and metastasis, it is also important to develop TMPRSS4 inhibitor as an anticancer target.
TMPRSS4 gene is also over-expressed in malignant thyroid neoplasms. Therefore, The gene is proposed as a diagnostic and prognostic marker in such types of cancer (non-patent references 3 and 4).
Up to date, various compositions for treating cancer have been studied, which have been mainly focused on the inhibition of cancer specific marker. However, the studies on TMPRSS4 considered as a target of cancer treatment have not been actively undergoing.
The present inventors have studied to develop an anticancer agent to inhibit metastasis by suppressing cancer cell infiltration by inhibiting TMPRSS4 over-expressed specifically in cancer cells. In the course of the study, the inventors prepared a 2-hydroxyarylamide derivative and confirmed that the compound had excellent effect of inhibiting TMPRSS4, leading to the completion of this invention.